Synthetic peptides inducing immunogenic cell death

Abstract

The disclosure relates to TSP-1-derived peptides capable of inducing immunogenic cell death, in particular immunogenic cancer cell death. It further relates to uses of such peptides, in particular to prepare a pharmaceutical composition to allow or improve the efficiency of a therapy of cancer in a subject in need thereof.

1 . A method of inducing immunogenic cell death in the treatment of cancer, comprising contacting a cancer cell with a synthetic TSP-1-derived peptide. 
     
     
         2 . The method according to  claim 1 , wherein said synthetic TSP-1-derived peptide is a compound or a pharmaceutical acceptable salt thereof comprising a hexapeptide sequence of formula (I):
   -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -  (I)
   wherein:
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6  are independently linked to each other according to formula (I) via peptide bonds or at least one pseudopeptide bond; 
 X 1  is a residue chosen in the list consisting of substituted or unsubstituted phenylalanine, substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, or substituted or unsubstituted homo-phenylalanine; 
 X 2  is a residue chosen in the list consisting of substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, substituted or unsubstituted phenylalanine, homo-phenylalanine, homo-meta-tyrosine, homo-para-tyrosine or homo-ortho-tyrosine; 
 X 3  is a residue chosen in the list consisting of substituted or unsubstituted valine, substituted or unsubstituted alanine, substituted or unsubstituted leucine, substituted or unsubstituted isoleucine; 
 X 4  is a residue chosen in the list consisting of substituted or unsubstituted valine, substituted or unsubstituted alanine, substituted or unsubstituted leucine, substituted or unsubstituted isoleucine; 
 X 5  is a residue chosen in the list consisting of substituted or unsubstituted methionine or any amino acid with similar properties such as a methylated homo-cysteine, lysine, norleucine, leucine or isoleucine; 
 X 6  is a residue chosen in the list consisting of substituted or unsubstituted tryptophan, substituted or unsubstituted hetero-tryptophan, substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, substituted or unsubstituted phenylalanine, or substituted or unsubstituted naphthyl-alanine; and 
 X 1  is the N-terminal side of the molecule of formula (I), X 6  is the C-terminal side of the molecule of formula (I). 
   
     
     
         3 . The method according to  claim 1 , wherein said peptide is selected from PKHB1 (SEQ. ID. No 2), PKT16 (SEQ. ID. No 17), PKTD10 (SEQ. ID. No 25), PKD10 (SEQ ID No 21), PKTDi2-FF (SEQ. ID. No 34) and PKTD10-X-RNMe (SEQ. ID. No 27). 
     
     
         4 . The method according to  claim 1 , wherein said peptide is selected from PKHB1 (SEQ. ID. No 2), PKT16 (SEQ. ID. No 17) and PKTD10 (SEQ. ID. No 25). 
     
     
         5 . The method according to  claim 1 , wherein cancer is selected from the group consisting of adrenal cortical cancer, anal cancer, bile duct cancer, multiple myeloma, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, Castleman disease, cervical cancer, colorectal cancer, endometrial cancer, esophagus cancer, gallbladder cancer, gastrointestinal carcinoid tumors, Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer, mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, melanoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, vaginal cancer, vulvar cancer, and uterine cancer. 
     
     
         6 . A method for inducing immunogenic cell death in tumour cell in vitro, comprising contacting the tumour cell with the cell in vitro with a synthetic TSP-1-derived peptide. 
     
     
         7 . A method for preparation of tumour cells that are immunogenic upon cell death, the method comprising a step of treating said cells with a synthetic TSP-1-derived peptide. 
     
     
         8 . A tumour cell contacted with a synthetic TSP-1-derived peptide, according to the method of  claim 6 , wherein the tumour cell is configured for the treatment of cancer. 
     
     
         9 . An injectable pharmaceutical composition comprising the tumour cell treated with a synthetic TSP-1-derived peptide according to  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         10 . The method of  claim 2 , wherein X 3  is valine. 
     
     
         11 . The method of  claim 2 , wherein X 4  is valine.